How to best manage HIV patient?

How to best manage HIV patient? 1 2 Treatment Treatment Failure success HIV therapy = a long life therapy

Why do we want to change a suppressive ART? Side effect Comorbidities Reduce drug burden How to modify ART? Reservoir 2

Viral load Concepts in Induction Maintenance ART Induction Maintenance strategy Nb drugs required Depending on - HIV - RNA - CD4 - HIV DNA Which antiviral potency do we need - to maintain viral suppression - CD4 above 500 /mm3 - without enlarging reservoir? 2 5 log drop Which markers can we use? Viral DNA? Activation markers? Time

Newer efficacious and well tolerated ARVs with higher potency and genetic barrier to resistance Simplication with drug burden reduction? Dual Therapy? Monotherapy Triple Therapy Dual Therapy Triple therapy needed to ensure efficacy and limited emergence of resistance 1 Drugs with relatively low potency and genetic barrier to resistance 1. Perez-Valero I, et al. J Antimicrob Chemother. 2011;66:1954 62.

Switching therapy Objective : maintain viral suppression Decrease drug burden Decrease/ prevent toxicity Simple regimen Robust regimen Reconstitutes ART and resistance history The switched regimen has to include potent and robust drugs Do not let a drug in a position of functionnal monotherapy Do not keep resistant drugs that cumulates toxicity and cost

EFV + LPV/r (n=250) % of patients EFV + 2 NRTI (n=250) LPV/r + 2 NRTI (n=253) ATV/r QD + FTC/TDF (n=30) ATV BID + RAL BID (n=63) LPV/r BID + FTC/TDF (n=105) LPV/r BID + RAL BID (n=101) DRV/r QD + RAL BID (n=112) ATV/r QD + FTC/TDF (n=61) ATV/r QD + MVC QD (n=60) Modern dual-therapy studies : 48-week results 100 HIV-1 RNA <200 copies/ml HIV-1 RNA <50 copies/ml 80 60 40 20 0 ACTG 5142* SPARTAN PROGRESS ACTG 5262 Study 1078** Created from 1. Portsmouth S, et al. AIDS 2011, Rome, Italy. Oral presentation TUAB0103; 2. Riddler SA, et al. NEJM 2008;358:2095 106; 3. Kozal MJ, et al. HIV Clin Trials 2012;13:119 30; 4. Reynes J, et al AIDS Res Hum Retro. 2012 Aug 3. [Epub ahead of print]. DOI: 10.1089/aid.2011.0275; 5. Taiwo B, et al. AIDS 2011;25:2113 22; 6. Mills A, et al. AIDS 2012, Washington, USA. Oral Presentation TUAB0102.

Dual therapy Summary of safety outcomes in studies of dual-therapies in ARV-naïve patients* Study Regimen Follow up Lipids Renal Bone Other ACTG 5142 1 LPV/r + EFV 96 weeks Elevated Not reported Not reported - PROGRESS 2 LPV/r + RAL 96 weeks Elevated Improved Improved CPK SPARTAN 3 ATV + RAL 96 weeks Neutral Not reported Not reported Bilirubin ACTG 5262 4 DRV/r + RAL 48 weeks Elevated Not reported Not reported - Study 1078 5,6 ATV/r + MVC 96 weeks Not reported Not reported Improved Bilirubin

Patients (%) PI/r monotherapy Monotherapy with LPV/r* 1 100 MONARK Initial therapy M03-613 Induction/Maintenance OK04 Simplification 80 60 40 20 NAÏVE SUPPRESSED (SHORT ) SUPPRESSED (LONG ) 0 0 16 32 48 0 16 32 48 64 80 96 Week Discontinued On study, HIV-1 RNA >400 copies/ml 0 12 24 Wk On study, HIV-1 RNA 50 400 copies/ml On study, HIV-1 RNA <50 copies/ml 36 48 *Boosted PI monotherapy is an off-label approach. Short-term suppression: 24 weeks; 2 Long-term suppression: >6 months. 3 Adapted from 1. Arribas JR, EACS 2009, Cologne, Germany. Oral Presentation; 2. Cameron WD, et al. J Infect Dis. 2008;198:2234 40; 3. Arribas JR, et al. JAIDS 2005;40:280 7.

MONET: Primary Efficacy Analysis: HIV RNA <50 copies/ml at Week 48 Per Protocol analysis (PP) Primary analysis Intent to Treat analysis (ITT) 100-1.6%; lower limit 95%CI: -10.1% -1%; lower limit 95%CI: -9.9% 90 87.8% 86.2% 85.3% 84.3% HIV RNA <50 by Week 48 (%) 80 70 60 50 Table EFF 4-5 40 30 20 10 0 DRV/r + 2NRTI (PP) DRV/r mono (PP) DRV/r + 2NRTI (ITT) DRV/r mono (ITT) N=123 N=123 N=129 N=127 J. Arribas et al, AIDS 2010

MONOI Primary Endpoint W48 J. Arribas et al, IAS Conference, Cape Town, SA, 21 July 2009, TUAB106-LB DRV/r Who are the patients with VL< 50 cp/ml in DRV/r? Patients with low VL and low DNA DRV/r + NRTIs

ENCORE1: 400-mg EFV Noninferior to 600-mg EFV With TDF/FTC for Initial ART Randomized, double-blind, placebo-controlled, noninferiority phase III trial Part of ongoing effort to identify ARVs effective at lower doses (and cost) Stratified by clinical site and HIV-1 RNA at screening (< 100,000 or 100,000 copies/ml) ART-naive pts, CD4+ 50-500 cells/mm 3, HIV-1 RNA > 1000 copies/ml (N = 636) EFV* 400 mg + placebo + TDF/FTC 300/200 mg (n = 324) EFV* 600 mg + TDF/FTC 300/200 mg (n = 312) Wk 48 HIV-1 RNA < 200 c/ml at Wk 48, % NC = F 90.0 85.8 No significant difference in SAEs between treatment arms More pts with AEs for EFV 600 mg vs EFV 400 mg (47.2% vs 36.8%; P =.008) More pts discontinued EFV 600 mg due to AE vs EFV 400 mg (1.9% vs 5.8%; P =.010) Puls R, et al. IAS 2013. Abstract WELBB01. *EFV administered as 200-mg tablets.

Is HIV cure achievable?

Decrease plasma HIV RNA to lowest replication Decrease reservoir Drug free remission : Functional cure Drug burden decrease: Reduce ARV Eradicate reservoir Sterilizing cure

Is Cure achievable? Elite controllers Never treated Special phenotype: HLA /Strong CD4 and CD8 response/high level cytokine towards HIV/Preserved central memory cells/low immune activation Berlin patient : CCR5 defective stem cell graft Mississipi baby Visconti patients Treated at early stage of infection Chronic long term patients? Salto

Mississipi baby 37 Born 35 weeks gestation ;mother tested at delivery low VL 2423 cp/ml ART started at H31. 13 000 cp/ml up M18 then lost to FU M24 : functionnal cure 100 000 Viral load evolution (c/ml) 10 000 1 000 100 HIV RNA : undetectable CV plasmatique indétectable ELISA negative HIV DNA: undetectable Régime ARV 1 : ZDV/3TC/NVP (31 heures - 7 jours) Régime ARV 2 : ZDV/3TC/LPV/r (7 jours - 18 mois) Arrêt des ARV 10 0 5 10 15 20 25 30 Mois Batterie d analyses virologiques ultra-sensibles Arrêt ARV Persaud D, CROI 2013, Abs. 48LB

Visconti Patients Post ART controllers 12 patients treated at PHI ART Duration (med ): 35mths Duration Off ART : 5 years CD4 count - pre ART 489 ( 371-955) - at ART stop: 931 (354-1639 -last value : 837( 388-1598 HIV RNA - preart : 5.0 log ( 3-7.3) - last value : 1.7 log ( 1.7-2.4) After > 6 years OFF ART Median RNA= <20 copies/ml Median DNA = 83 copies/m PBMC Very limited CD8 activation A. Saez-Cirion et al., # F-126 CROI 2011 (Boston)

SALTO ANRS 116 Treatment interruption in early treated patients with CD4 > 350 and VL < 50 000 cp/ml 95 patients Age 40 years (IQR: 36 45). Pre-cART values CD4 : 454 /ml (392 576) VL : 4.3 log 10 cp/ml (3.9 4.5) CD4 nadir : 382 /ml (340 492). Duration of cart : 5.3 years (4.0 6.0)- Baseline values CD4 count : 813 cells/ml (695 988), DNA : 206 copies/10 6 PBMCs (IQR: 53 556) 12 months post TI - 7/95 patients still had a VL<400 cp/ml KP: 7.5%, CI: 3.7-14.6) - 4 kept a VL<400 copies/ml up to 36 months; - All had CD4 cell >500/mm 3 - HIV DNA was the only significant predictor of maintaining VL < 400 cp/ml med value : < 10 vs 233 cp / 10 6 PBMCs p < 0.001 Piketty et al, J Med Virol, 2010;82:1020-3 Assoumou et al, CROI 2013

Why do we need a Cure for HIV? To control the HIV pandemics How? Current AntiRetroVirals Reduce drug burden NO AIDS Persistence of HIV Reservoirs Can we decrease the HIV reservoirs and stop ART? Functional Cure? or eradicate HIV Sterilizing Cure?

Potential strategies to reduce HIV reservoirs Maraviroc Anti-inflammatory drugs - Statins - OH-Chlorochin Systemic Inflammation Massive CD4 T-cell depletion Bacterial translocation Pre-Probiotics ARV Intervention - Intensification - Nevirapine CD8 CD4 Cellular Immunity Immune Intervention - Anti-HIV vaccine - IL7 Viral Co- Infections Immune Activation Residual Replication Antiviral drugs Gene therapy DC CD4 Anti-co-stimulatory molecules - anti PD1 / anti PDL1 - anti-ctla4 - anti-cd137 HIV Reservoirs Latency Quiescent T cells activation - IL7 Pre/post-transcriptional factors disruption - HDACi - HMBA

Goals of Anti RetroViral Therapy Normalized life expectancy Normal CD4/CD8 Minimal Immune Activation/ inflammation No viral replication Minimal HIV Reservoirs Prevent HIV Transmission

Need for individualized therapy in Long-term virological suppression Minimal ART Maximal viral suppression Control of HIV Plasma Compartments Reservoirs Optimal immune status and minimal activation AGING Cardiovascular risk Cancer Cognitive disorders Renal disorders ART Toxicity Cardio vascular risk Mitochondrial toxicity Bone disorders CNS?

HIV is a global challenge Scientific Medical Social Human rights and dignity

Test any individual with sexual life Early treatment Maximal viral suppression Restore immunity > 500 CD4 Treatment as confort for life Treatment as a control for epidemics